High density fibrous polymers suitable for implant

ABSTRACT

This invention includes malleable, biodegradable, fibrous compositions for application to a tissue site in order to promote or facilitate new tissue growth. One aspect of this invention is a fibrous component that provides unique mechanical and physical properties. The invention may be created by providing a vessel containing a slurry, said slurry comprising a plurality of natural or synthetic polymer fibers and at least one suspension fluid, wherein the polymer fibers are substantially evenly dispersed and randomly oriented throughout the volume of the suspension fluid; applying a force, e.g., centrifugal, to said vessel containing said slurry, whereupon said force serves to cause said polymer fibers to migrate through the suspension fluid and amass at a furthest extent of the vessel, forming a polymer material, with said polymer material comprising polymer fibers of sufficient length and sufficiently viscous, interlaced, or interlocked to retard dissociation of said polymer fibers.

RELATED APPLICATION

This application is a Continuation of U.S. patent application Ser. No.13/481,575, filed on May 25, 2012, now U.S. Pat. No. 8,633,299, entitledHIGH DENSITY FIBROUS POLYMERS SUITABLE FOR IMPLANT, which is aContinuation of U.S. patent application Ser. No. 13/027,025, filed onFeb. 14, 2011, now U.S. Pat. No. 8,188,229, entitled HIGH DENSITYFIBROUS POLYMERS SUITABLE FOR IMPLANT, which is a Divisional of U.S.patent application Ser. No. 11/741,611, filed on Apr. 27, 2007, now U.S.Pat. No. 7,910,690, entitled HIGH DENSITY FIBROUS POLYMERS SUITABLE FORIMPLANT, which is a Continuation of U.S. patent application Ser. No.11/178,175, filed on Jul. 8, 2005, now U.S. Pat. No. 7,214,765, entitledHIGH DENSITY FIBROUS POLYMERS SUITABLE FOR IMPLANT, which was aContinuation of PCT International Patent Application S.N.PCT/US04/19805, filed on Jun. 19, 2004, and designating the U.S.,entitled High Density Fibrous Polymers Suitable for Implant, which was aContinuation-in-Part of U.S. patent application Ser. No. 10/601,216,filed on Jun. 20, 2003, now U.S. Pat. No. 6,974,862, entitled HIGHDENSITY FIBROUS POLYMERS SUITABLE FOR IMPLANT, all of which are assignedto the same assignee as this invention, and whose disclosure isincorporated by reference herein.

BACKGROUND OF THE INVENTION

The invention generally relates to medical devices and procedures. Theinvention more particularly concerns a polymeric construct havinginterlaced and interlocked fibers and products formed from the fibrouspolymer.

To better treat our aging population, physicians are looking for new andbetter products and methods to enhance the body's own mechanism toproduce rapid healing of musculoskeletal injuries and degenerativediseases. Treatment of these defects has traditionally relied upon thenatural ability of these types of tissue to repair themselves. In manyinstances the body is unable to repair such defects in a reasonabletime, if at all. Advances in biomaterials has allowed for the creationof devices to facilitate wound healing in both bone and soft tissuesdefects and injuries. Such devices are used in tissue regeneration astissue (e.g., bone) graft scaffolds, for use in trauma and spinalapplications, and for the delivery of drugs and growth factors.

Bone and soft tissue repair is necessary to treat a variety of medical(e.g., orthopedic) conditions. For example, when hard tissue such asbone is damaged as a result of disease or injury, it is often necessaryto provide an implant or graft to augment the damaged bone during thehealing process to prevent further damage and stimulate repair. Suchimplants may take many forms (e.g., plugs, putties, rods, dowels,wedges, screws, plates, etc.), which are placed into the tissue.Typically, such implants can be rigid, flexible, deformable, or flowableand can be prepared in a variety of shapes and sizes. For non-rigidstructural repair materials (e.g., putties and pastes) to beconveniently used, they must be capable of being formed into a varietyof complex shapes to fit the contours of the repair site. An accuratelyconfigured implant that substantially fills the defect site will enhancethe integration of natural bone and tissue to provide better healingover time. The prior art discloses medical implants that comprise, atleast partly, collagen (to be discussed later).

Collagen is the most abundant protein found in the body. The uniquechemistry of collagen makes it an ideal polymer for structural andhemostatic applications in both clinical and diagnostic settings.Collagen, like all proteins, is comprised of amino acids linkedcovalently through peptide or amide linkages. The sequence of the aminoacids, or the primary structure, outlines the three-dimensionalstructure of the protein, which in turn dictates the function, andproperties of the molecule. Collagen is composed of three peptide chainsassociated in a triple helical orientation. These triple helicesassociate to form fibrils, which ultimately make up connective tissueand other structural members.

Collagen has been used in a number of applications in the art. Forexample, one application is for use in hemostatic devices for thestoppage of bleeding, such as is described in U.S. Pat. No. 5,310,407(Casale) and U.S. Pat. No. 4,890,612 (Kensey). However, neither teachesthe use of native insoluble fibrous collagen. In U.S. Pat. No.5,425,769, Snyders, Jr. discloses a biocompatible and bioresorbable bonesubstitute with physical and chemical properties similar to bone,consisting of reconstituted fibrillar collagen within a calcium sulfatedi-hydrate matrix. The ratios of calcium sulfate and collagen areadjusted for each application and the bone substitute is molded in situto form a solid phase. Snyders Jr. discloses an implant that remainsmalleable only for a brief period, as the combination of fibrillarcollagen and calcium sulfate di-hydrate matrix forms a hard composition.Furthermore, the collagen as described in the '769 patent is neitherinterlocked, nor interlaced, relying on the calcium sulfate to lendstructural integrity.

The polymer utilized for the implant may be combined in application witha biologically active agent to enhance the tissue healing response orenhance the mechanical properties of the implant (e.g., U.S. Pat. No.4,776,890 (Chu)). Chu discloses a process for creating matrix ofcollagen containing mineral particles, such that when wetted, the matrixis malleable and retains its integrity. The matrix as claimed by Chuincorporates up to 10% of the mass as collagen, and relies on thephysical characteristic of the particles comprising the bulk of thematrix to lend the integrity, and upon exposure to fluids, would lead todissociation of the material unless a cross-linking step is performed.However, this cross-linking process is disfavored by Chu, as it woulddiscourage bone tissue ingrowth.

Huc et al. (U.S. Pat. No. 5,331,092) describes a process for preparingmedical pads by grinding collagen, acidifying with acetic acid,homogenizing, molding and freeze-drying. The pad formed would readilyfall apart upon exposure to aqueous fluids and thus requirescross-linking. The cross-linked pads hold together but have limitedmechanical strength limiting their usefulness to hemostatic pads.

Nigam (U.S. Pat. No. 4,948,540) described a process for preparing acollagen dressing material by creating a slurry comprised of an acidsolubilized collagen and a non-solubilized natively cross-linkedcollagen. The resultant slurry was molded, and freeze-dried into a pad.The pad did not have sufficient mechanical properties due to itsexcessive porosity and thus was compressed at a pressure of15,000-30,000 psi and optionally cross-linked. To improve strength dueto lack of fiber-to-fiber interaction, the device is compressed withoutinterlacing of the individual fibers. The compression serves to compressin only one dimension, placing the fibers in close proximity in oneorientation, rather than interlacing the fibers.

Li (U.S. Pat. No. 5,206,028) described a process for preparing a densecollagen membrane by first freeze-drying a collagen dispersion of randomfibers to form a sponge. This sponge was then humidified, compressed andsubjected to chemical cross-linking. The resultant sponge was strong,having randomly entangled masses of fibers going in all directions. Thisdevice as described by Li lacks interlacing of the insoluble collagen asthe aqueous dispersion is lyophilized without first interlacing theinsoluble components.

Li (U.S. Pat. No. 6,391,333) described a process wherein sheets oforiented biopolymeric fibers are formed into sheets by capturing them ona spinning mandrill that was rotated in a fibrous collagen slurry. Thefibers were then compressed to force them closer together so they couldbe dried, preferably while in contact with a gluing agent. The sheet wasthen cut from the mandrill, inverted and cross-linked to form a sheet.Additional sheets could be individually stacked on top of each other tocreate thicker devices with greater mechanical strength. The device asconstructed has fibers substantially aligned in parallel planes, andlacks equiaxial interlacing.

In PCT application WO 98/35653, Damien describes a process for preparingan implantable collagen putty material by acidifying a collagen solutionto a pH of between 3.0 to 6.0. This produces a non-fibrous dough likematerial that can be used to suspend graft material. At higher pH, thecollagen precipitates out, becoming crumbly with a consistency of wetsand.

It is well known to utilize a centrifuge or filtration press as a partof a rinsing procedure, or a ‘wash step’ to remove insoluble componentscontained within the solution. Nishihara (U.S. Pat. No. 3,034,852)describes a process to solubilize previously insoluble collagen fiberswithout denaturation of the protein structure by using hydrolyticenzymes. In the examples, the author describes separation of the fibersfrom the wash solution by centrifugation or filtration press methods,the fibers are then brought back into solution. Additionally, thefibers, which are separated using this method are reconstituted fiberswhich tend to be small in size.

Highberger, et. al. (U.S. Pat. No. 2,934,446 and U.S. Pat. No.2,934,447) describe a method, as well as, the physical preparation ofcollagen fiber masses to form leather-like sheets from hide scrapsunusable in the traditional leather making process. This psuedo-leathermay support small colonies of cells but would be unsuitable for tissueingrowth. The method of concentration used is a precipitation technique,which creates a fiber dispersion. This slurry/dispersion as describedincluded random clumps of undispersed or entangled fibers. Highbergercombines a unique fiber that coacts with a high dissolved solids contentcollagen solution to form well knit, or leather like sheet. In the '447patent, Highberger further refines the process of the '446 patent byincorporating a kneading step, which works the dough material to makethe product free from lumps, the kneading necessarily disrupts anyinterlacing or interlocking fibers prior to precipitating thesolubilized collagen.

SUMMARY OF THE INVENTION

This invention includes malleable, biodegradable, fibrous compositionsfor application to a tissue site in order to promote or facilitate newtissue growth. One aspect of this invention is a fibrous component(e.g., collagen, chitosan, alginate, hyaluronic acid, poly-lactic acid,poly-caprolactone, and polyurethane) which provides unique mechanicaland physical properties, as will be discussed.

Fibers may be suspended within a suspension fluid (preferably aqueous)forming a relatively homogenous slurry/dispersion. This dispersionpreferably has a low solid content whereby the organizing process, e.g.,centrifugation, causes the material to have preferable mechanical andphysical properties.

The physical properties may include, but are not limited to, injectable,flexible, compression resistant, or elastic properties. Biologicproperties may include, but are not limited to, conductive or inductiveproperties for hard and soft tissues. Additionally, in a preferredembodiment, additives (e.g., fibers, particulate, or gels) may be usedto further tailor the material properties.

In a preferred embodiment, the degree of centrifugation is specified todictate the physical properties of the resulting material;alternatively, or in combination, a rehydration step may be tailored toaffect the physical properties of the material, as will be discussed. Asan example, the properties of this material may be tailored such thatexposure to rehydration liquids or bodily fluids (e.g., blood) willrender the material to be self-supporting. That is, the material willnot readily slump under its own weight, even though it is readilymoldable by hand pressure. This can be particularly useful during aprocedure where the entire wound site is not immediately secured orenclosed by hard tissue or other constraint. Additionally, theimplantable embodiments may contain biologically active agents, whichmay aid osteoconductivity or osteoinductivity.

In a preferred method, the material may be created by providing a vesselcontaining a slurry, said slurry comprising a plurality of natural orsynthetic polymer fibers and at least one suspension fluid, wherein thepolymer fibers are substantially evenly dispersed and randomly orientedthroughout the volume of the suspension fluid, or at least exhibiting nosignificant organization or preferred orientation; applying a force,e.g., centrifugal, to said vessel containing said slurry, whereupon saidforce serves to cause said polymer fibers to migrate through thesuspension fluid and amass at a furthest extent of the vessel, generallyat a wall or similar surface of the vessel, forming a polymer material,with said polymer material comprising polymer fibers of sufficientlength and sufficiently viscous, interlaced, or interlocked to retarddissociation of said polymer fibers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 A, B, and C are enlarged, representative diagrams depicting thearrangement of interlacing and interlocking fibers of the presentinvention, wherein a force (e.g., centrifugal) is applied in orientationrepresented by the arrow.

FIG. 2 depicts a hydrated malleable mass 400 of interlaced fibers 110.

FIG. 3 depicts a human extremity 600 that has been surgically opened toreveal bone 610. A hydrated malleable mass 500 is being inserted into anexposed osseous defect 620.

FIG. 4 depicts an insertion of an interlaced fibrous putty 720 into aconfined tissue defect 700. The applied force 710 of the insertion isconducted by the interlaced fibers of the putty, forcing it intointimate contact with the walls defining the tissue defect.

FIGS. 5A, B, and C depict a cylinder 1100 of interlaced fibers 110. Thefibers are represented by open space defined by the dimensions of thecylinder. The interlocking of the interlaced fibers 110 supports,confines, and locks the particulate material 120 and biologically activeagent 130 within a spatial conformation. The Cylinder 1100 is insertedinside of a preformed structure or cage 1110 creating a spinal implant1120.

FIG. 5D depicts spinal implant 1120 being inserted into a defined space1210 within two vertebral bodies 1200.

FIG. 6 depicts dry sheet 1300 of interlaced fibers 110. The fibers arerepresented by open space defined by the dimensions of the sheet. Theinterlocking of the interlaced fibers 110 supports, confines, and locksthe particulate material 120 and biologically active agent 130 within aspatial conformation. As the dry sheet 1300 becomes hydrated, it becomesa conformable mass 1310 that can be approximated to the irregulartopography of the transverse processes 1320 of the vertebrae.

FIG. 7 depicts the injection of a hydrated malleable mass 920 ofinterlaced fibers from a syringe 800 into a tissue defect 1000.

FIG. 8A depicts hollow intermedullary nail 1500 having openings 1510containing graft material 1520 composed of interlaced, interlockedfibers and particulate.

FIG. 8B depicts the femoral portion of artificial hip prosthesis 1550having a hollow stem portion 1560 having openings 1510 containing graftmaterial 1520 composed of interlaced, interlocked fibers andparticulate.

DETAILED DESCRIPTION OF THE INVENTION

This invention is a malleable, biodegradable, fibrous composition forapplication to a tissue site in order to promote new tissue growth. Oneaspect of this invention is a fibrous component (e.g., collagen,chitosan, alginate, hyaluronic acid, polylactic acid, poly-caprolactone,and poly-urethane, etc.) (see table 1) which provides unique mechanicaland physical properties, as will be discussed.

Fibers (e.g., collagen, chitosan, alginate, and hyaluronic acid), may beobtained, for the example of type I collagen, from bovine hide, whichhave been processed in a manner known by those skilled in the art. As anexample, the hides are stripped from the animal carcass and the corium(i.e., the intermediate layer of an animal hide between the grain andthe flesh sides) is subsequently split from the rest of the hide. Thecorium is limed using a calcium hydroxide solution to remove extraneousorganic material. The limed corium is then neutralized using an acidsolution and the excess salt produced is serially rinsed (e.g., withwater). The neutralized corium is then ground using a mill typeapparatus to tear apart the corium into fibers. This process maintainsthe native cross-links within the collagen. (During the aging process ofthe live animal, intermolecular and interfibrillar bonds are naturallyformed between collagen fragments. These naturally occurring bonds arewhat distinguish the fibers of collagen as natively cross-linked fibersas opposed to reconstituted fibers of collagen). The fibers aresuspended within a suspension fluid (preferably aqueous) forming arelatively homogenous slurry/dispersion. This dispersion preferably hasa solid content ranging from 0.25 to 10%, but most preferably in therange of 3 to 5% by weight.

The resultant slurry is concentrated by centrifugation; preferably, attemperatures below 60 degrees Celsius to avoid degradation of thecollagen and subsequent gelatin formation. Speed and therefore force, aswell as time can be varied to create the desired extent of fiberinterlacing, as will be discussed later. The slurry can be spun underforces of about 500×g (times gravity) to forces as high as about30,000×g and for times ranging from 10 seconds to 96 hours. Preferably,the suspension is spun at forces of 500×g to 10,000×g and times of 1minute to 24 hours. Most preferably the suspension is spun at 3000×g forabout 5 minutes. This creates, in a preferred embodiment, a paste orputty-like structure containing interlocked or interlaced collagenfibers, as will be discussed, that may be molded and dried by eitherevaporation to create a high density non-porous unit, or bylyophilization to maintain the three dimensional structure and porosity.An additional preferred embodiment comprises a material that is aflowable, yet dense, material, which may be injected or otherwisemolded. This moldable embodiment may be cast into a mold, or in situ, aswill be discussed.

Referring to FIG. 1A, the interlacing phenomenon occurs as the fibers 27and 28 migrate down through the suspension fluid, and the individualfibers interlace among other fibers, herein represented by interlacingfiber 28 becoming interlaced with other fibers 27, entering a region 29bordered by other fibers 27. In FIG. 1A, it is desirable to start with alow solids content (e.g., below 10%) slurry so that the fibers areuniformly distributed and freely moving prior to centrifugation.Entangled clumps of fibers (not shown) may interfere with properinterlacing and should be minimized by starting with the lowconcentrations. Interlacing is a non-directional interlocking of fibers27 randomly in three dimensions throughout the material, as opposed tolayer-like or directional entanglement of the fibers, as will bediscussed. FIG. 1B depicts interlacing 33 (represented by the zonewithin the dashed circle), as the low concentration fiber mix migratesand gradually intertwines itself during centrifugation, but does so in athree dimensional type of formation. Without wishing to be bound to anyparticular mechanism or explanation, it is believed that this phenomenonoccurs because there is a nearly uniform load on all of the fibers 27,with the exaggerated gravitational load (i.e., from the centrifuge)tending to move the fiber 28, without necessarily rotating it. This, inturn, causes the fibers 27 and 28 to eventually coalesce and at leastpartially thread themselves together, to some degree as the interlacingfiber 28 enters the region 29 bordered by the other fibers 27.

As the interlacing 33 continues, the fibers come into contact with thesurface of the container, in the centrifuge, or other fibers alreadycompressed with the surface. As the fibers continue the migration, andeventually “pile up” or amass, they become further interlaced andeventually the fibers 28 may be deformed or bent as the pressure ofother migrating fibers builds.

Referring to FIG. 1C, as the pressure builds, and the fibers 27 and 28compress, the interlacing step is completed, and the deformation of thefibers causes them to interlock 34 (depicted by the dashed circle). Itis this dual interaction of interlacing and interlocking that results inthe unique properties of certain embodiments of the present invention.

In these various embodiments, the fibers are not externally pressedtogether (not shown), which causes the higher end of the fibers to bepressed downward (causing alignment) by the externally applied force(e.g., a platen). The non-uniform force ultimately causes a directionalor anisotropic fiber bundle; similarly, the evaporation of the fluidfrom a preferential direction causes fiber bundling and alignment at theevaporating surface/interface.

Additionally, interlacing restricts the motion of fibers within a unitduring rehydration, since all external surfaces are comprised of fiberswhich intrude into the material itself (not shown), thereby retardingdisassociation of fibers from the unit upon contact with a fluid. Uponrehydration the dried structure forms a paste or putty-like materialsimilar in characteristic to that of the pre-dried material, as will bediscussed.

Likewise, interlacing of the fibers also provides greatermulti-directional consistency (i.e., isotropy) in the mechanicalproperties as opposed to directional mingling of fibers. That is, theinterlacing is three dimensional, and therefore provides uniformproperties in the three dimensions; whereas the directional materialspreviously discussed yield materials with properties along the fiberaxis (e.g., the plane of flattening or evaporation) that are verydifferent from the properties perpendicular to the fiber axis.

Interlacing also provides biologic advantages over directionalentanglement by providing an equiaxial structure (or a structural thatmore resembles an equiaxed structure's lack of directionality) forcellular infiltration as well as an advantageous platform for tissueformation. A structure that allows cells to infiltrate uniformly in alldirections may improve overall tissue organization, and may also avoid,in soft tissue regeneration, the directional bundling common in fibrousscar tissue.

Centrifuging materials such as fibrous collagen will also createchemical linkages aside from physical interlacing that serve toreinforce the resulting matrix. In the particular case for collagen, thecentrifugal force brings individual fibers and fibrils into closemolecular proximity, and re-establishes non-covalent forces such ashydrogen bonding, hydrophobic/hydrophillic interactions, andelectrostatic interactions, that these individual fibers and fibrilspreviously embodied in the native, pre-extracted tissue. Theseadditional chemical linkages may act to create a pseudo-molecular weightincrease to the matrix. Thus, the combinatorial effects of physicalinterlacing and chemical bonds impart unique cohesive properties andviscosity to these fibrous putties.

Although centrifugation is a preferred process, a similar interlacingmay be accomplished by placing a low concentration slurry (e.g., lessthan 15% polymer) into a closed container and exposing it to a globalforce such as multi-axis gyroscopic mixing. This multi-axis mixingprocess causes flocculation of the fibers as they migrate through thesuspension fluid towards the center of the closed container wherein theybecome interlaced with one another. The clumps of interlaced fibers thatamass may then be exposed to a force that extracts a portion of thesuspension fluid thereby allowing the fibers within the interlacedclumps to become interlocked with each other.

To improve the migration of fibers and prevent clumping during theinterlacing process, as described above and expanded upon below, it ispreferred to incorporate a percentage (e.g., 0%-50% by mass of fibers)of one or more lubricants (e.g., biocompatible oils, hydrogels, liquidpolymers, low-molecular weight polymers, glycosaminoglycans,surfactants, waxes, fatty acids, fatty acid amines and metallicstearates such as zinc, calcium, magnesium, lead and lithium stearate,etc.) into the suspension fluid. A lubricant is defined as a substance,which is capable of making surfaces smooth or slippery. Thesecharacteristics are due to a reduction in friction between the polymerfibers to improve flow characteristics and enhance the knitting andwetting properties of the fibers. The lubricant may be liquid or solidand may be suspended or dissolved in a carrier solvent (e.g., water,alcohol, acetone, etc.). Additionally the lubricant may only becomelubricious under shearing force or change in temperature. The lubricantmay remain in its entirety in the final invention; may be partiallyremoved in the dehydration/desolvation process; or, may be washed out orremoved by methods known in the art during further processing.Lubricants that remain in the final invention may be biologically activeagents or may form microstructures. Preferred lubricants includeTween-80, hyaluronic acid, alginate, glycerin or soluble collagen withthe most preferred being acid soluble collagen such as Semed S producedby Kensey Nash Corporation (Exton, Pa.).

Additional ways in which to add lubricity include physically orchemically altering the surface of the fibers making up the composition.Such alterations can be achieved through chemical or physical attachmentof a lubricious substance to the fibers, temperature induced phasechanges to the surfaces of the fibers or partial solubilization of thefibers through alteration of the pH and/or conductivity of the freefluid or use of a percentage of solvent for the fibers within the freefluid. Other methods of creating lubricity are known to those skilled inthe art, and are embraced by this disclosure.

During rehydration, the material absorbs liquid (e.g., water, bodilyfluids, blood, etc.) to the limits of the void (i.e., pore) volume.Since a large portion of the surface fibers are intruding in thematerial, the inward ends are locked by mechanical and/or frictionalmeans. This aspect of the interlacing phenomenon causes the material toremain intact while the fluid ingresses, with minimal fiber liberationto the non-absorbed liquid. In contrast, directionally pressed materialslose surface fiber during rehydration, since they are not anchored orinterlocked (i.e., they lay parallel to the surface of the material).

In these various embodiments, the material will freely absorb liquiduntil the approximate pre-dried volume is attained; at which point thematerial is in a state of pseudo-equilibrium. This state is achievedbecause the interlocked fibers are re-hydrated, returning to theirnatural state (i.e., centrifuged position). The continued absorption ofliquid will, over an extended period of time, cause the fibers tode-interlace (i.e., the working free of interlaced fibers). The actionof partial de-interlacing, i.e., the movement of fibers againstfrictional and other mechanical locking within a region without totalfiber separation, allows shifting or movement of zones that remaininterlaced. Resistance to fiber movement within the interlaced zones,combined with the frictional forces of the de-interlaced regions givesthe material the paste or putty-like consistency. In contrast,traditional collagen materials would rapidly dissociate into there-hydrating fluid.

The continued exposure to liquids will cause the material to swellbeyond the aforementioned pseudo-equilibrium, and impart somede-interlacing, however, this absorption occurs at a rate significantlyless than the rate prior to achieving pseudo-equilibrium. This attributein itself, may be useful, because certain embodiments of this inventionmay be sized for particular types of defects, and the near equilibriumstate will be more easily achieved without careful monitoring of therehydration level of the material.

Whether the optimum absorption level is achieved may be moot, becausethe size can be altered or molded by applying pressure (e.g., squeezing)to the material to cause the expulsion of some of the absorbed liquid.This feature is attractive, since it renders the material tailorablewith regard to size, shape and consistency. Additionally, in a preferredembodiment, some or all of the liquid may be absorbed in vivo, therebycausing intimate contact along the entire defect cavity.

As shown in FIG. 2, the consistency of the various embodiments of theinvention allows them to form a malleable putty/paste 400 that canconform to unique shapes and contours encountered in tissue-engineeringapplications. The interlocking of the interlaced fibers 110 retardsdissolution of the device, allowing it to be used in unconfined wounds(e.g., segmental defects as shown in FIG. 3). FIG. 3 depicts a humanextremity 600 that has been surgically opened to reveal bone 610, ahydrated malleable mass 500 is being inserted into an exposed osseoussegmental defect 620.

Similarly, the interlocking of the interlaced fibers 110 retardsdissolution of the device, allowing it to be used in confined woundspaces (e.g., a tissue void as shown in FIG. 4). FIG. 4 depicts aninsertion of an interlaced fibrous putty 720 into a confined tissuedefect 700. The applied force 710 of the insertion is conducted by theinterlaced fibers of the putty, forcing it into intimate contact withthe walls defining the tissue defect.

The presence of interlaced fibers 110 in the devices makes itparticularly suited to those tissue defects exposed to irrigation,especially at volumes and/or flow rates where current state of the artputties fail (e.g., disintegrate, disassociate, break apart). Theembodiment of FIG. 2 is suitable for, but not limited to: cell culturesupport and transfer, cartilage defect filling, bone void filling, softtissue augmentation (e.g., removal of dermal creases) and periurethralbulking to combat urinary incontinences arising from such conditions asintrinsic sphincter deficiency. Additional possibilities include but arenot limited to use as a spinal cage filler (as shown in FIG. 5),depicting a cylinder of interlaced fibers. The fibers are represented byopen space defined by the dimensions of the cylinder. The interlockingof the interlaced fibers may support, confine, and lock the particulatematerial and biologically active agent within a spatial conformation (aswill be discussed later). The cylinder 1100 of FIG. 5A, is insertedinside of a preformed structure 1110 of FIG. 5B, or cage creating aspinal implant 1120 of FIG. 5C, which may then be implantedsubstantially as shown in FIG. 5D.

An alternate use of the putty is depicted in FIGS. 8A and 8B, whereinthe putty material is inserted inside of an intermedullary nail 1500(FIG. 8A) and the femoral shaft portion 1560 of a hip prosthesis 1550(FIG. 8B). At least a portion of the rigid implant, that which extendsinto the bone, would be porous, or hollow and containing holes 1510through the wall of the implant capable of receiving the putty 1520 andallowing ingrowth of host tissue. This would allow bone to grow throughand ultimately in and around the rigid implant, thereby effectivelyanchoring it to the rest of the surrounding bone. The putty utilized asa graft material may include particulates and/or biologically activeagents. It is recognized that the particulate material itself may befunctional as a biologically active agent (e.g. Demineralized BoneMatrix, etc.) The novel concept of providing a prosthesis containing ahollow zone(s) capable of receiving graft material is useful in thecreation of dental implants or any other implant, which requiresanchoring to host tissue such as an ocular prosthesis or mechanicalheart valve.

Alternatively, FIG. 6 is another possible use for the putty, depicted asa graft overlay to retain osteoconductive/osteoinductive graftingmaterial (e.g., harvested bone chip, ceramics, etc.) during a transverseprocess spinal fusion (as shown in FIG. 6). FIG. 6 depicts dry sheet1300 of interlaced fibers 110. The fibers are represented by open spacedefined by the dimensions of the sheet. The interlocking of theinterlaced fibers 110 may support, confine, and lock the particulatematerial 120 and biologically active agent 130 within a spatialconformation (as will be discussed later). As the dry sheet 1300 becomeshydrated, it becomes a conformable/malleable mass 1310 that can beapproximated to the irregular topography of the transverse processes1320 of the vertebrae. In these additional applications the malleablecharacteristics of the hydrated device will allow it to conform to theunique shaped chambers of the spinal cage or the irregular topography ofthe transverse process surgical site. In a transverse process surgicalprocedure the implant covers and secures the graft material (not shown)in place.

In another embodiment (not shown) the putty is preformed into a cup andutilized to retain graft material placed in and around the acetabulumduring a hip reconstruction. The putty is then sandwiched between thehost bone and the artificial cup that will receive the prosthesis. Ifadditional toughness is required, the cup can be cross-linked to providea flexible article that may further feature shape-memory. Additionally,the putty can be packed around the stem of the prosthesis prior to itsinsertion into the long bone channel. If desired, a novel prosthesis (asdescribed above for FIGS. 8A and 8B) with a stem having a hollowcage-like appearance can be utilized. The putty is inserted into thecage wherein it is then dried and sterilized. Optionally, the driedputty can be cross-linked to prevent egress from the prosthesis. Thissame novel cage-like structure can be utilized for nails placed in theshaft of long-bones.

In another embodiment, the putty material contains reinforcing materialssuch as long threads, meshes or other fibers (not shown). Theinterlocking of the interlaced fibers supports, confines, and locks thereinforcing material within a spatial conformation. This retards thereinforcing material from migrating within or dissection from the puttyor paste. This can be used to alter mechanical properties (e.g.,compressive strength) as well as enhance resistance to disassociation offibers form the construct. Additionally, the putty may improve thebiocompatibility of the reinforcing material (e.g., improved cellularmigration within or adhesion to a mesh). The reinforcing material may becentered within the construct, located on or just below one or moresurfaces or interspersed throughout the entire construct.

In another embodiment the interlocking of the interlaced fibers is usedto control the location and delivery of biologically active agents(e.g., growth factors, hormones, BMP, drugs, cells, viruses, etc.) (seetable 2). The unique equiaxial formation of the device controls flow offluid (e.g., blood, interstitial, etc.) within the device allowing fortailored release properties. The biologically active agents could belocated within or supported between the fibers making up the device.Additionally, the biologically active agents could be mechanically orchemically attached or bonded to the fibers or suspended within ahydration fluid. This hydration fluid may contain a soluble polymer thatsuspends or binds the biologically active agent. Additionally, thehydration fluid containing the soluble polymer may be removed leavingthe soluble polymer as a solid sheet or coating adhered to the fibers,an open laced network of strands adhered to the polymer fibers; avelour, felting or loosely woven sheet adhered to the polymer fibers; oras a porous foam or microstructure suspended between the fibers. Inaddition to supporting a biologically active agent, the hydrated solublepolymer can function as a lubricant to aid in partial de-interlacing ofthe polymer fibers during molding or implantation.

It is also conceived that in one embodiment of this invention thematerial can contain an additive that can be used to help deliver orretain the previously described biologically active agents. As anexample, the interstices of the gross fibrous structure could beinvested with a soluble polymer as defined above, e.g., a chemotacticground substance, such as the velour of hyaluronic acid. A velour ofchemotactic ground substance could accomplish several biochemical andbiomechanical functions essential for wound repair. For example, sincehyaluronic acid is extremely hydrophilic, it may be valuable for drawingbody fluid (e.g., blood, bone marrow) or other fluid-based biologicallyactive agents into the fibrous device. Upon hydration, the hyaluronicacid can become an ideal carrier for pharmacological or biologicallyactive agents (e.g., osteoinductive or osteogenic agents such as thebone morphogenetic protein (BMP) and other bone-derived growth factors(BDGF)) by providing for chemical binding sites, as well as by providingfor mechanical entrapment of the agent as the velour forms a hydrogel.

It is also conceived that a source of growth factors (e.g.,platelet-rich plasma, bone marrow cells, etc.), whether synthetic,autologous or allograft in origination, can be delivered with the deviceof this invention (e.g., incorporated into the implant duringmanufacturing or integrated into the device prior to implantation). Forexample, it is known that one of the first growth factors to initiatethe cascade leading to bone regeneration are platelet-derived growthfactor (PDGF) and transforming growth factor-beta (TGF-β). Each of thesegrowth factors is derived from the degranulation of platelets at thewound, defect or trauma site. It is believed that increasing thepresence of such platelets at the wound or trauma site can increase therate of healing and proliferation needed to regenerate tissue (e.g.,bone).

The application of platelet-rich plasma (PRP) is one way to deliver ahighly concentrated dose of autologous platelets. PRP is easily preparedby extracting a small amount of the patient's blood and processing it,for example, using gradient density centrifugation, to sequester andconcentrate the patient's platelet derived growth factors. Otherpreparation methods remove water from the buffy coat (i.e., coagulatedblood coating) and utilize filtering systems to concentrate plateletsand fibrinogen. It is believed that applying PRP or other autologousgrowth factors to the wound site in conjunction with the subjectinvention will increase the amount of PDGF and TGF-8 available forjump-starting the healing process. PRP can be prepared for procedureswith small volumes of blood, drawn by the doctor or nurse presurgically.Typically, 40-100 ml of blood are drawn preoperatively and placed in aPRP preparation unit. SmartPREP (Harvest Technologies Corp., Norwell,Mass.) and UltraConcentrator (Interpore Cross, Irvine, Calif.) aredevices that have been shown to effectively produce PRP for OR, officeimplant, and periodontal uses.

Once the PRP is prepared, other additives (e.g., activator, growthfactor, drug, chemical, bone, etc.) can be added to the plasma. Forexample, to infuse the implant material of this invention with a PRP gelpreparation, the ratio of ingredients would include a higher proportionof PRP to allow the PRP to more effectively flow through and permeatethrough the putty material. It is also conceived that the de-hydratedputty can be inserted into the PRP preparation unit (e.g., centrifuge,concentration unit). In this fashion, the platelets can be concentratedright into or onto at least a portion of the implant directly. Forexample, some PRP devices include a centrifuge for separation of theblood components. The biomaterial implant could be positioned within thecentrifuge such that the desired blood constituent is directed into theimplant material during processing.

Other autologous materials can also be incorporated into and used inconjunction with the subject invention (e.g., autologous bone marrowcells (BMC)). Bone marrow contains osteogenic progenitor cells that havethe ability to form and repair bone. The marrow can be harvested anddispersed into single cell suspensions. The cells can then beconcentrated (e.g., through filtering, centrifucation) or used as is.The resulting mixture can be diluted and implanted into the wound site,incorporated into the implant material, or delivered by the deliverysystem (e.g., syringe) with the materials of the subject invention.

In another embodiment, the interlocking of the interlaced fibers is usedto control the location and orientation of particulate componentscompounded into the fibrous material (e.g., ceramic, glass,glass-ceramic, metals, tricalcium phosphate, Hydroxylapatite, calciumsulfate, autologous bone graft, allograft bone matrix, polymers,microspheres, microcapsules, hyaluronic acid, collagen, chitosan,alginate, poly-lactic acid, poly-glycolic acid, poly-caprolactone,polyurethane, etc). The particulate components may additionally carry orserve to deliver biologically active agents. The interlacing supports,confines, and locks the particulate components within a spatialconformation. This retards the particulate from migrating within ordisassociating from the putty or paste. (When the fibrous material iscombined with a fine powdered ceramic, the consistency is morechalk-like than that of putty or paste formed with larger ceramicparticulate.) A fibrous slurry containing particulate may beconcentrated using centrifugation as mentioned above, or particulate maybe added as a solute to a rehydrating solvent. Alternatively, theparticulate may be mechanically incorporated (e.g., kneaded) into theinterlaced fibrous putty. The resulting material may be implanted ordried and rehydrated with a volume of liquid to yield a desired densityor consistency to the paste or putty. It should be noted that previouslydried putty is suitable for implantation dry wherein it is rehydrated bybody fluids (e.g., blood).

When adding particulate, the addition of a soluble polymer to increasethe viscosity of the aqueous solution prevents premature separation orstratification of the particulate from the collagen fibers in the finalproduct. Additionally, the fluid containing the soluble polymer can beremoved, leaving the particulate entrapped within the soluble polymer asa coating on the fibers or suspended between the fibers.

When porous particulates are used, the fibers randomly penetrate thepores and become interlaced along with the fibers, creating a singlecontinuous network of fibers and particulate. The particulate may createa type of hub with fibers radiating out to other hubs. This creates aunique structure wherein particulate loss is reduced. Additionally,cells migrating into the structure along the fibers may be guided to theincorporated particulate.

The concentrations of the putty or paste, as well as the extent ofinterlacing between fibers that result from centrifuging, producecharacteristics that range from smooth injectable gels to highly compactmasses with elastic type qualities. For instance, the centrifuge may beused to spin down fibrous slurry into blocks or uniquely shaped molds(e.g., tubes, ears, nose, cones, brick, plate, disk, ellipse, sheet,membrane, wedge, pin, rod, cylinder, roles, cup, sphere, semi-sphere,pyramid and a frustum of a cone, wedge or pyramid, etc). Additionally,material properties provided by the action of partial de-interlacing (asdescribed previously) of centrifuged fibrous slurry allow the materialto be: 1) injected through a syringe; 2) pressed between plates; 3)injection molded; 4) rolled out into flat sheets; 5) carved and/orformed like clay; or 6) aerated. This partial de-interlacing allows foran additional way in which to form shapes listed above.

In an embodiment, there may be a benefit to the creation of aninterlaced and interlocked fibrous composition as described above,further featuring a plurality of pores. The pores may be created bytechniques known in the art (e.g., a gas expansion process, a freezedrying process, etc.). The pores may be of a closed cell morphology,open cell and intercommunicating morphology, or a combination of both.The pores may be of a regular, ordered size or shape, or alternativelymay vary in size or shape. The shape and size of the pore may bemanipulated through various pore formation techniques known in the art.

For example, the flow caused by the movement of the fibers duringcentrifuging may create equiaxial and/or elongated pores (dependant offiber length) within the final product post-drying (e.g.,lyophilization, air-dried, etc.) Additionally, freeze rate, freezedirection, temperature gradients and insolubles (fibers and particulate)can be used to control crystal formation, that in turn controls poresize, shape and orientation. Furthermore, as the liquid freezes to solidcrystals, the fibers and particulates have an impact on pore formationas they potentially interfere with crystal growth. As the temperature ofa mixture is lowered, crystals form within the fluid surrounding thefibers and particulate. As the crystals grow they force the fiber andparticulate material aside, thereby effectively increasing theconcentration of the material between the crystals. The growth of thecrystals may be disrupted as they come in contact with the fibers andparticulate. This interruption of crystal growth, either stops thegrowth of the crystal or forces them to grow around the particles in anirregular fashion. After solidification the crystals of the frozenliquid are removed by methods know in the art (e.g. vacuum drying orleaching) leaving irregular pores.

Orientation of fibers, along with the interlacing (to keep the fibers asone mass), that allows putty-like dispersions to be injected through asyringe. This is depicted in FIG. 7, wherein the syringe 800 injects ahydrated malleable mass 920 of interlaced fibers into a tissue defect1000. The capability of the fibrous implant material in the form of thehydrated malleable mass 920 to be delivered via syringe 800 makes itsuitable for use in laparoscopic, arthroscopic and endoscopicprocedures. These minimally invasive surgical procedures utilizecannulas and trocars to remotely treat or repair a variety of injuriesor maladies. It should be understood that the fibrous implant's uniqueviscosity allow for the delivery of the material to remote sites withinthe body. Once delivered, the material can remain intact and stable atthe delivery location for a period of time post implantation.

It should also be noted that use of reinforcing materials (polymer mesh,tricalcium phosphate, etc.) or addition of biologically active agents(growth factors, DBM, cells, drugs, etc.) may be employed as aparticulate or other addition. Additions may be made in an effort toincrease the viscosity of the pre-centrifuge process liquid, but theaddition may also be used to coat the fibers. This fiber coating may beemployed to tailor the inner environment of the material, and mayimprove, e.g., the osteoconductivity or osteoinductivity. These coatingsor other additions may be uniformly dispersed throughout the fibrousstructure, or more sporadic. In a preferred embodiment, the coating oradditive will create a microstructure, adherent to the fibrousmacrostructure. In certain embodiments with microstructural additionsthe microstructure may be more prominent at junction points, or regionswhere several fibers come in contact with each other. In a preferredembodiment these microstructurally coated junctions serve to attract andnourish the inbound cells.

In another embodiment, the centrifuge process yields a material with aviscous high-density structure that, in itself, is useful for surgicalprocedures. For example, this unique fiber arrangement, regardless ofthe degree of interlacing or interlocking, if any, renders the materialsuitable for hand molding or injecting via syringe. The uniquethree-dimensional nature of this structure of this material exhibitsproperties not seen in the art.

In another embodiment, the materials made by these various processes maybe cross-linked to impart improved characteristics such as: mechanicalstrength (e.g., suturablity, compression, tension, etc.), andbiodurability (e.g., resistant to enzymatic and hydrolytic degradation).This may be accomplished using several different cross-linking agents,or techniques (e.g., thermal dehydration, EDC, aldehydes (e.g.,formaldehyde, gluteraldehyde, etc.), natural cross-linking agents suchas genipin or proanthocyanidin, and combinations thereof). Each type ofcross-linking agent/technique or combinations thereof imparts diversemechanical and biological properties on the material. These propertiesare created through the formation of unique chemical bonds thatstabilize the construct. This stabilization greatly increases theconstruct's ability to hold a shape and conformation, thereby,preserving the interlaced relationship between the fibers.

As an example of cross-linking, the construct may be placed in 100 mMEDC solution contained in pH 5.4 MES buffer for 1 minute to 24 hours,preferably 4 hours. This creates a chemical bond between amino andcarboxyl acid groups to form amide linkages. The device is then rinsedand dried by either lyophilization or simple evaporation.

This newly stabilized device, containing interlaced fibers, has superiormechanical and biological properties as compared to prior artconstructs. The interlaced fibrous structure guides cellular ingrowthcreating newly regenerated tissue that more closely approximates naturaltissue than can be achieved via a random structure. Additionally, thethree dimensional interlaced structure allows for the occurrence ofdirectional, biomechanical stimulus useful in the regeneration of tissuewhich is exposed to mechanical motion. This can be seen in tissues suchas cartilage, intervertebral discs, joint meniscus, blood vessel, heartvalves, or the like.

In various embodiments of the invention the collagen putty, that hasbeen formed or shaped by any methods known to those skilled in the art,can be cross-linked to create uniquely shaped biodurable medical devices(not shown). The devices may take on forms such as sheets, tubes, roles,blocks, cylinders brick, plate, disk, ellipse, membrane, wedge, pin, rodcup, sphere, semi-sphere, cone, pyramid, frustum of a cone, wedge orpyramid or pads useful for tissue augmentation, replacement, or repair.Additionally the devices can be shaped into unique anatomically specificshapes (e.g. nose, ear, chin, etc).

In one embodiment the interlocking of the interlaced fibers allows ahighly concentrated putty to be rolled flat and stressed in threedimensions simultaneously, producing an intact sheet that can becross-linked; whereas directionally oriented fibers would tear apart orexperience separation during the flattening process (not shown).Therefore, this material would be useful in such applications as, butnot limited to dura repair, skin grafting procedures, hernia repair,rotator cuff repair, ligament repair or bladder support or repair.

In another embodiment (not shown) the sheet produced in the previousembodiment is rolled prior to cross-linking to create a unique spiralconfiguration having a plane separating each successive revolution ofthe sheet. The plane provides unique compressive qualities, that whencombined with the compressive qualities of the cross-linked interlacedfibers, is ideal for applications receiving directional compressiveloads. These applications include but are not limited to joint meniscus,intervertebral disk and articular cartilage. In another embodiment theplane formed by the spiral configuration can be filled with materials toenhance its mechanical or biologic characteristics (e.g., reinforcingmaterials, particulates, biologically active agents, natural andsynthetic polymers).

Various of these shaped embodiments may also be manufactured incomposite laminate form. That is, flat sheet or shaped embodiments, maybe affixed to other materials, by pressing, gluing, or means known tothose skilled in the art. These macro-composites may combine thematerials of these embodiments with material, i.e., with higherstrength, osteo conductivity, resorbability, etc.

In another embodiment (not shown) a fibrous collagen slurry can be spundown into a mold that approximates the gross anatomy of a tissue ororgan (e.g., blood vessel, heart valve, ear, nose, breast, finger-bones,long bone, acetabular cup, etc.) prior to cross-linking. Theinterlocking of the interlaced fibers, formed during this process,provides superior shape holding characteristics due to the uniqueresistance to fiber disassociation, as previously described. Constructsmade using oriented fibers defined in prior art do not hold crispmargins. Therefore, material in this embodiment would be useful as, butnot limited to, devices for cosmetic and reconstructive surgery,intervertebral disks, joint meniscus and hollow tissues and organs(e.g., intestine, esophagus, ureter, etc.).

In another embodiment (not shown) a fibrous collagen slurry can be spundown into a mold containing a structure or component (e.g., ring, mesh,particulate, screw, rod, screen, etc.) to which the interlaced fibersmigrate around, thereby creating a mechanical lock, after whichcross-linking may occur. The interlocking of the interlaced fiberssupports, confines, and locks the structure or component within aspatial conformation.

In another embodiment (not shown) the partial de-interlacing of zoneswithin a putty or paste facilitates compression or injection of thematerial into or around structures such as, but not limited to: molds,screws, rings, rods, cavities, meshes or screens. Injected into a tubemold the material would be suitable as a vascular graft or nerveconduit. Injected into more massive and possibly complex shapes, thematerial would be suitable for applications such as: intervertebraldisks, soft tissue augmentation, ocular prosthesis, joint meniscus, bonevoid or soft tissue filler, and applications in plastic andreconstructive surgery.

Additionally, material may contain reinforcing materials such as longpolymer threads or meshes or may include particulates or biologicallyactive agents. (e.g., growth factors, hormones, bmp, drugs, cells,viruses, etc.) Additionally, the biologically active agents could belocated within fibers making up the putty, mechanically or chemicallyattached to the fibers making up the putty, between the fibers, orsuspended within a hydration fluid or second soluble polymer intermixedwith the fibers of the putty material. The biologically active agentsand/or soluble polymer intermixed with the fiber may be added prior toor after cross-linking.

It is conceived the interlaced polymer material may be manufactured bythe centrifugation process heretofore described, and may be sterilizedand packaged, or alternatively dried (e.g., by lyophilization orevaporative processes) then sterilized and packaged for later use. It isalso recognized that either the wet product or the dry product may beterminally sterilized.

The following examples are given for purposes of illustration to aid inunderstanding the invention and it is to be understood that theinvention is not restricted to the particular conditions, proportionsand reagents set forth therein.

Example 1

Fibrous Collagen, 4% solids in water by weight, pH 5.3-5.9, was placedmixed with powdered (6 micrometers) β-tricalcium phosphate until ahomogeneous mixture was achieved. This dispersion was centrifuged at3200×g for 2 minutes to reduce the mixture 40% by volume. Thesupernatant was poured off and discarded. The “pellet” was removed fromthe centrifuge tube, placed in a mold, and freeze-dried. This sameprocessed was followed with a larger particle size (500-1000micrometers) β-tricalcium phosphate. When centrifuged under the sameconditions the resulting dispersion was reduced 60% by volume.

Example 2

Fibrous Collagen, 4% solids in water by weight, pH 5.3-5.9, was placedin a centrifuge tube. The dispersion was centrifuged at 8000×g for 24hours. The supernatant was poured off. The solution was reduced by ˜90%volume loss. This dough-like mass was then shaped into a mold andfreeze-dried. The resultant sponge was then cross-linked using a thermaldehydration to lock in the molded shape. Upon rehydration, the resultantsponge held its shape and showed high resistance to compression. It wasalso noted that the sponge contained some elastic properties. Theseelastic properties allowed the sponge to be warped, twisted, andmanipulated after which it returned to its original confirmation,thereby displaying shape memory. This may be useful when insertingthrough a narrowing.

Example 3

Fibrous Collagen, 4% solids in water by weight, pH 5.3-5.9, was placedin a centrifuge tube. The dispersion was centrifuged at 8000×g for 4-5hours. The supernatant was poured off. The solution was reduced by ˜80%volume loss. This dough-like mass was then rolled flat using a rollingpin or a two roller system to create a high fiber density sheet. Thesheet was freeze-dried and cross-linked using a 100 mM EDC solution (pH5.4) in water. The sheet was allowed to soak in the cross-linkingsolution overnight and then serially rinsed 3× for 2 hours withagitation in water. This sheet exhibited high resistance to tearing andripping.

TABLE 1 Examples of Biodegradable Polymers for Construction of theDevice Aliphatic polyesters Bioglass Cellulose Chitin CollagenCopolymers of glycolide Copolymers of lactide Elastin FibrinGlycolide/1-lactide copolymers (PGA/PLLA) Glycolide/trimethylenecarbonate copolymers (PGA/TMC) Hydrogel Lactideltetramethylglycolidecopolymers Lactide/trimethylene carbonate copolymersLactide/ε-caprolactone copolymers Lactider/σ-valerolactone copolymersL-lactide/dl-lactide copolymers Methyl methacrylate-N-vinyl pyrrolidonecopolymers Modified proteins Nylon-2 PHBA/γ-hydroxyvalerate copolymers(PHBA/HVA) PLA/polyethylene oxide copolymers PLA-polyethylene oxide(PELA) Poly (amino acids) Poly (trimethylene carbonates) Polyhydroxyalkanoate polymers (PHA) Poly(alklyene oxalates) Poly(butylenediglycolate) Poly(hydroxy butyrate) (PHB) Poly(n-vinyl pyrrolidone)Poly(ortho esters) Polyalkyl-2-cyanoacrylates PolyanhydridesPolycyanoacrylates Polydepsipeptides Polydihydropyrans Poly-dl-lactide(PDLLA) Polyesteramides Polyesters of oxalic acid Polyglycolide (PGA)Polyiminocarbonates Polylactides (PLA) Poly-1-lactide (PLLA)Polyorthoesters Poly-p-dioxanone (PDO) Polypeptides PolyphosphazenesPolysaccharides Polyurethanes (PU) Polyvinyl alcohol (PVA)Poly-β-hydroxypropionate (PHPA) Poly-β-hydroxybutyrate (PBA)Poly-σ-valerolactone Poly-β-alkanoic acids Poly-β-malic acid (PMLA)Poly-ε-caprolactone (PCL) Pseudo-Poly(Amino Acids) Starch Trimethylenecarbonate (TMC) Tyrosine based polymers

TABLE 2 Examples of Biological, Pharmaceutical, and other Therapies orAgents Deliverable via the Present Invention Adenovirus with or withoutgenetic material Alcohol Amino Acids L-Arginine Angiogenic agentsAngiotensin Converting Enzyme Inhibitors (ACE inhibitors) Angiotensin IIantagonists Anti-angiogenic agents Antiarrhythmics Anti-bacterial agentsAntibiotics Erythromycin Penicillin Anti-coagulants Heparin Anti-growthfactors Anti-inflammatory agents Dexamethasone Aspirin HydrocortisoneAntioxidants Anti-platelet agents Forskolin GP IIb-IIIa inhibitorseptifibatide Anti-proliferation agents Rho Kinase Inhibitors(+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl) cyclohexaneAnti-rejection agents Rapamycin Anti-restenosis agents Adenosine A_(2A)receptor agonists Antisense Antispasm agents Lidocaine NitroglycerinNicarpidine Anti-thrombogenic agents Argatroban Hirudin GP IIb/IIIainhibitors Anti-viral drugs Arteriogenesis agents acidic fibroblastgrowth factor (aFGF) angiogenin angiotropin basic fibroblast growthactor (bFGF) Bone morphogenic proteins (BMP) epidermal growth factor(EGF) fibrin granulocyte-macrophage colony stimulating factor (GM-CSF)hepatocyte growth factor (HGF) HIF-1 insulin growth factor-1 (IGF-1)interleukin-8 (IL-8) MAC-1 nicotinamide platelet-derived endothelialcell growth factor (PD-ECGF) platelet-derived growth factor (PDGF)transforming growth factors alpha & beta (TGF-.alpha., TGF-beta.) tumornecrosis factor alpha (TNF-.alpha.) vascular endothelial growth factor(VEGF) vascular permeability factor (VPF) Bacteria Beta blocker Bloodclotting factor Bone morphogenic proteins (BMP) Calcium channel blockersCarcinogens Cells Chemotherapeutic agents Ceramide Taxol CisplatinCholesterol reducers Chondroitin Collagen Inhibitors Colony stimulatingfactors Coumadin Cytokines prostaglandins Dentin Etretinate Geneticmaterial Glucosamine Glycosaminoglycans GP IIb/IIIa inhibitors L-703,081Granulocyte-macrophage colony stimulating factor (GM-CSF) Growth factorantagonists or inhibitors Growth factors Bone morphogenic proteins(BMPs) Core binding factor A Endothelial cell Growth Factor (ECGF)Epidermal growth factor (EGF) Fibroblast Growth Factors (FGF) Hepatocytegrowth factor (HGF) Insulin-like Growth Factors (e.g. IGF-I) Nervegrowth factor (NGF) Platelet Derived Growth Factor (PDGF) RecombinantNGF (rhNGF) Tissue necrosis factor (TNF) Tranforming growth factorsalpha (TGF-alpha) Transforming growth factors beta (TGF-beta) VascularEndothelial Growth Factor (VEGF) Vascular permeability factor (UPF)Acidic fibroblast growth factor (aFGF) Basic fibroblast growth factor(bFGF) Epidermal growth factor (EGF) Hepatocyte growth factor (HGF)Insulin growth factor-1 (IGF-1) Platelet-derived endothelial cell growthfactor (PD-ECGF) Tumor necrosis factor alpha (TNF-.alpha.) Growthhormones Heparin sulfate proteoglycan HMC-CoA reductase inhibitors(statins) Hormones Erythropoietin Immoxidal Immunosuppressant agentsinflammatory mediator Insulin Interleukins Interlukin-8 (IL-8)Interlukins Lipid lowering agents Lipo-proteins Low-molecular weightheparin Lymphocites Lysine MAC-1 Methylation inhibitors MorphogensNitric oxide (NO) Nucleotides Peptides Polyphenol PR39 ProteinsProstaglandins Proteoglycans Perlecan Radioactive materials Iodine-125Iodine-131 Iridium-192 Palladium 103 Radio-pharmaceuticals SecondaryMessengers Ceramide Somatomedins Statins Stem Cells Steroids Surfactantstween triton polysorbate witconate sulfonic tea sodium oleate ThrombinThrombin inhibitor Thrombolytics Ticlid Tyrosine kinase Inhibitors ST638AG-17 Vasodilators Histamine Forskolin Nitroglycerin Vitamins E C YeastZiyphi fructus

The inclusion of groups and subgroups in Table 2 is exemplary and forconvenience only. The grouping does not indicate a preferred use orlimitation on use of any drug therein. That is, the groupings are forreference only and not meant to be limiting in any way (e.g., it isrecognized that the Taxol formulations are used for chemotherapeuticapplications as well as for anti-restenotic coatings). Additionally, thetable is not exhaustive, as many other drugs and drug groups arecontemplated for use in the current embodiments. There are naturallyoccurring and synthesized forms of many therapies, both existing andunder development, and the table is meant to include both forms.

1-32. (canceled)
 33. A biocompatible composition suitable forimplantation into a living being, comprising a network of randomlyinterlocked polymer fibers, wherein said polymer fibers are arrangedwith respect to a particulate material to maintain said particulatewithin a spatial conformation within the biocompatible composition, andretard disassociation of the particulate from the biocompatiblecomposition, wherein the network of fibers is configured to be combinedwith a fluid.
 34. The biocompatible composition of claim 33, whereinsaid polymer fibers are arranged to support, confine or lock saidparticulate material within said spatial conformation and retarddisassociation of said particulate from said biocompatible composition.35. The composition of claim 33 wherein the network of fibers isinitially in a dry form, and upon being combined with said fluid,results in a rehydrated implantable composition, wherein the fluid isselected from at least one of blood, bone marrow aspirates, stem cells,or concentrates thereof.
 36. The composition of claim 35, whereupon saidparticulate is kneaded into the biocompatible fibrous network prior toimplantation.
 37. The composition of claim 33 wherein at least a portionof said polymer is at least one biopolymer selected from the groupconsisting of collagen, chitosan, alginate, hyaluronic acid, poly-lacticacid, poly-glycolic acid, poly-caprolactone, and polyurethane.
 38. Thecomposition of claim 33, further comprising at least one of abiologically active agent, or a lubricant.
 39. The composition of claim33, wherein said particulate further comprises at least one of abiologically active agent, a microsphere or a microcapsule.
 40. Thecomposition of claim 33, wherein said particulate comprises a pluralityof pores.
 41. The composition of claim 40, wherein said fibers arearranged in such a manner so as to be at least partially interlacedwithin said pores of the particulate.
 42. The composition of claim 33,wherein said particulate is at least one of ceramic, glass,glass-ceramic, metals, tricalcium phosphate, hydroxylapatite, calciumsulfate, autologous bone graft, allograft bone matrix, demineralizedbone, polymers, microspheres, microcapsules, hyaluronic acid, collagen,chitosan, alginate, poly-lactic acid, poly-glycolic acid,poly-caprolactone, polyurethane or combinations thereof.
 43. Thecomposition of claim 33, further comprising a second polymer, saidsecond polymer being soluble, and wherein said polymer fibers aresurrounded by said second soluble polymer.
 44. The composition of claim43, wherein said second soluble polymer is arranged to providelubrication for said fibers, whereupon said composition becomespartially de-interlocked and shapeable.
 45. The composition of claim 33,being arranged as a bulk shape.
 46. The composition of claim 45, saidhulk shape is at least one of a brick, a plate, a disk, an ellipse, asheet, a membrane, a wedge, a pin, a rod, a cylinder, a roll, a tube, acup, a sphere, a semi-sphere, a cone, a pyramid, a frustum of a cone, afrustum of a wedge, and a frustum of a pyramid.
 47. The composition ofclaim 33, wherein said polymer fibers are partially de-interlocked,whereupon said composition becomes shapeable.
 48. The composition ofclaim 33, wherein said polymer fibers are cross-linked, saidcross-linking serving to provide shape memory to said composition. 49.The composition of claim 33, further comprising a reinforcing material.50. The composition of claim 49, wherein said reinforcing materialcomprises at least one of a mesh, screen or thread.
 51. A kit comprisinga) a concentration unit, and b) an implantable composition comprising aplurality of polymer fibers, wherein said polymer fibers are ofsufficient quantity and sufficiently interlaced or interlocked as toretard dissociation of individual polymer fibers upon implantation. 52.The kit of claim 51, wherein said implantable composition comprises adry network of randomly interlocked polymer fibers, and at least oneparticulate, wherein said polymer fibers are arranged with respect to aparticulate material to maintain said particulate within a spatialconformation within the biocompatible composition, and retarddisassociation of the particulate from the biocompatible composition,wherein the network of fibers is configured to be combined with a fluid.53. The kit of claim 51 wherein said concentration unit is configured tocreate a concentrate from a sample placed within the concentration unit,wherein said sample comprises at least one of blood, bone marrowaspirate, or stem cells.
 54. The kit of claim 53, wherein saidconcentration unit is configured for use in one of a centrifuge orfilter system.
 55. The kit of claim 51, wherein said implantablecomposition is added to said concentration unit prior to theconcentration occurring.
 56. The kit of claim 53, wherein saidconcentrate is removed from said concentration unit and directed ontosaid implantable composition at a time selected from prior toimplantation, after implantation, or concurrent with implantation. 57.The kit of claim 53, wherein said concentrate further comprisesbiologically active agents.